US3823181A - Novel 1-benzoyloxy-2-lower alkylamino-benzocycloalkane derivatives - Google Patents

Novel 1-benzoyloxy-2-lower alkylamino-benzocycloalkane derivatives Download PDF

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Publication number
US3823181A
US3823181A US00262623A US26262372A US3823181A US 3823181 A US3823181 A US 3823181A US 00262623 A US00262623 A US 00262623A US 26262372 A US26262372 A US 26262372A US 3823181 A US3823181 A US 3823181A
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Prior art keywords
tetralin
cis
group
dimethylamino
benzoyloxy
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Expired - Lifetime
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US00262623A
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Inventor
M Murakami
K Takahashi
T Mase
I Yanagisawa
Y Hirata
K Kubo
M Takeda
H Ino
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Yamanouchi Pharmaceutical Co Ltd
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Yamanouchi Pharmaceutical Co Ltd
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Priority claimed from JP46044491A external-priority patent/JPS516669B1/ja
Priority claimed from JP9849571A external-priority patent/JPS4867274A/ja
Priority claimed from JP10004971A external-priority patent/JPS4864060A/ja
Application filed by Yamanouchi Pharmaceutical Co Ltd filed Critical Yamanouchi Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/60—Naphthoxazoles; Hydrogenated naphthoxazoles

Definitions

  • R represents hydrogen atom or a lower alkyl group
  • R represents a lower alkyl group
  • R R and R are the same or different from each other and each represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, phenyl group, amino group, a lower alkylamino group, an acylamino group or nitro group
  • n is an integer of 1-3, and the non-toxic mineral acid salts thereof.
  • the compounds of this invention have a local anesthetic and analgesic action and are also useful in promoting the function of the stomach.
  • the present invention relates to novel benzocycloalkane derivatives. More particularly, the invention relates to the l-benzoyloxy-Z-lower alkylaminobenzocycloalkane derivatives represented by the formula OCO- Br I C I): (III) wherein R represents a hydrogen atom or a lower alkyl group; R represents a lower alkyl group; R R and R are the same or different from each other and each represents hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, phenyl group, amino group, a
  • the l-benzoyloxy-Z-lower alkylaminobenzocycloalkane derivatives of the formula (III) and the non-toxic mineral acid salts thereof, which are the compounds of this invention, are novel compounds and have excellent local anesthetic action.
  • the compounds of this invention can maintain a local anesthetic action even in the pH range of the gastric juice and thus they are quite suitable for curing gastritis and duodenitis.
  • Procaine, lidocaine, etc. have, hitherto, been known as the compounds having the local anesthetic action but it has been difficult to remove such gastric symptoms caused by acute or chronic gastritis, such as a stomach ache, a heavy feeling on stomach, belching, nausea, etc., by those conventional compounds. This is believed to be due to the fact that said compounds lose their local anesthetic activity at the gastric pH (about 2).
  • Oxethazine which has corrected this fault has been widely marketed.
  • oxethazaine has high local anesthetic action at the gastric pH as compared with aforesaid compounds, the action thereof is insufficient for relieving the ache caused by a dueodenal ulcer and also its local anesthetic action is unduly delayed (Progress in Medicinal Chemistry, 3, 387 (1963)).
  • misnamed l-benzoyl- H oxy, l-p-nitrobenzoyloxy, or 1-p-aminobenzoyloxy-2-dimethylamino Tetralin obtained by benzoylating the above compound are, in fact, 2-benzoyloxy-, Z-p-nitrobenzoyloxy and further 1 benzoyloxy-Z-dimethylaminotetrahydro- -p-aminobenzoyloxy-l-dimethylamino Tetralin.
  • naphthalene hydrochloride having a melting point of 176 Accordingly, although thenam'esof the compounds of C.
  • the compounds of this invention wherein R is an amino group can be obtained by reducing the compound where R is nitro group in a conventional manner if necessary.
  • the reaction is conducted by reacting the compound of the formula (I) with, usually equimolar or slightly excessive molar amount of the compound of the formula (II) or the reactive derivative thereof at the carboxyl group.
  • the reaction is conducted in water or a proper organic solvent.
  • the benzoic acid i.e. the compound of the formula (II)
  • the reaction can be conducted at room temperature in an organic solvent such as methylene chloride, chloroform, etc., under the presence of an almost equimolar amount of a carbodiimido compound such as dicyclohexylcarbodiimide.
  • the reaction is conducted by allowing the reactants to stand in an organic solvent such as benzene, toluene, etc., or by heating them in the solvent but a tertiary base such as pyridine, triethylamine, etc., may be added tothe reaction system.
  • an organic solvent such as benzene, toluene, etc.
  • a tertiary base such as pyridine, triethylamine, etc.
  • the reaction may be conducted by a so-called Schotten-Baumann reaction in the presence of an alkali hydroxide in an aqueous solvent-
  • the reaction may be usually conducted in an organic solvent suchas chloroform, benzene, etc., at room temperature or as the case may be under heating.
  • the compound of the formula (III) prepared by the aforesaid-reaction may be isolated by a conventional chemical operation such as a; filtration, concentration, recrystallization, column chromatography and the like.
  • the starting material of the formula (I) used in this invention there are the cis-form and the trans-form according to the steric configurations of the amino group and the hydroxyl group as well as the dl-form, the op tically active d-form, and l-form.
  • the compound having the corresponding steric and optical configuration is obtained.
  • the mixture of those isomers of the starting material are used in the reaction and the products may be separated by a fractional crystallization, column chromatography, optical resolution, etc.
  • the compound may be reduced by a conventional manner.
  • the reduction is carried out by heating the compound together with an iron powder and hydrochloric acid in water.
  • the compounds of this invention shown by the formula (III) may be obtained by other methods than those described above.
  • the compounds of the formula (III) may be also obtained by reacting the 2-amino 1 benzoyloxybenzocycloalkane derivatives represented by the formula wherein R R and R and n are as defined above with a lower alkylating agent such as methyl iodide, ethyl iodide, dimethyl sulfate, etc., by a conventional manner.
  • the compounds of the formula (HI) wherein R is hydrogen atom may be prepared by reacting a compound of the formula (IV) with a lower aldehyde such as formaldehyde, acetaldehyde, propionaldehyde, etc., to provide a corresponding Schiifs base followed by reducing.
  • a lower aldehyde such as formaldehyde, acetaldehyde, propionaldehyde, etc.
  • the compounds of the formula (111) wherein R is a lower alkyl group may be prepared by reacting the compounds of the formula (III) wherein R is hydrogen atom prepared by the above procedure and a lower alkylating agent such as methyl iodide, ethyl iodide, dimethyl sulfate, etc.
  • the compounds of the formula (III) of this invention wherein R and R are a methyl group may be obtained by heating the compounds of the formula (IV) or the oxazoline derivatives represented by the formula wherein R R and R and n are as defined above together with calculated or excessive amounts of formaldehyde and formic acid.
  • the starting materials of the formula (I) may be prepared by reacting the compounds of the formula (VI) with a lower alkylating agent such as methyl iodide, ethyl iodide, dimethyl sulfate, etc., or by reacting the compound of the formula (V1) with a lower aldehyde such as formaldehyde, acetaldehyde, propionaldehyde, etc., to form a corresponding Scanges base followed by reducing.
  • the compounds of the formula (I) wherein R and R are a methyl group may be obtained by heating a compound of the formula (VI) together with calculated or excessive amounts of formaldehyde and formic acid.
  • the R group .of the compounds lpf-this invention shown by. the formula (III) includes a hydrogen atom and a lower alkyl' group such as methyl group, ethyl group, isopropyl group, 'isobutyl group, tert-butyl group, amyl group, etc. Also, the R group includes a lower alkyl group such-as methyl group, ethyl group, isopropyl group, isobutyl group, tert-butyl group, andlamyl group.
  • the groups R R and R are the same or different from each other and each represents hydrogen atom; a halogen atom such as chlorine, bromine, etc.; a lower alkly group such 'as mehtyl group, ethyl group, isopropyl group, tert-butyl group, and amyl group; a lower alkoxy group such as methoxy group, ethoxy group, etc.; a substituted amino group such as monomethylamino group, monoethyl amino group, dimethylamino group, diethylamino group, acetoamino group, carbobenzoxyamino group; amino group; phenyl group; and nitro group.
  • a halogen atom such as chlorine, bromine, etc.
  • a lower alkly group such 'as mehtyl group, ethyl group, isopropyl group, tert-butyl group, and amyl group
  • a lower alkoxy group
  • Those compounds may be converted into the non toxic acid addition salts with a mineral acid such as hydrochloric acid, hydrobromic acid, phosphoric acid, or sulfuric acid.
  • a mineral acid such as hydrochloric acid, hydrobromic acid, phosphoric acid, or sulfuric acid.
  • the compounds of this invention are orally administered in the form of, e.g., tablets, capsulated form, powder, etc.
  • the clinical dosage of the therapeutic compounds of this invention to an adult is -20 mg. and the amount of the compound is orally administered 1-3 times in a day. The dosage thereof is properly controlled by the condition and age of the patient.
  • the stimulating action of the gastric motility is denoted as when the'spontaneous motility of the stomach continued longer than ZO minutes" and is denoted as when it did not continue.
  • Example 1 In 5 ml. of benzene was dissolved 3.8 g. of cis-l-hydroxy- Z-dimethylamino Tetralin and than 2 ml. of a benzene solution containing 3.1 g. of benzoyl chloride was added to the solution. The mixture was allowed to stand overnight at room temperature and then refluxed for 4 hours. The reaction mixture was cooled, the crystals thus formed were recovered by filtration, and after washing them with a small amount of benzene, they were recrystallized from an ethanolethyl acetate solvent to obtain 4.3 g. of cis-1- benzoyloxyQ-dimethylaminotetralin hydrochloride having a melting point of 203-204 C. (melting point of 223 C. by means of a Micro-Melting Point Apparatus).
  • the former crystals were suspended in water and after adding to the suspension potassium carbonate, the mixture was extracted with ether. The extract was dried, mixed with ethanol and hydrochloric acid, and then the solvent was distilled off. By recrystallizing the residue from ethanol-ether, l-cis-l-benzoyloxy-2-dimethylamino Tetralin hydrochloride having a melting opint of 211- 212 C. (decomposed) was obtained.
  • Example 2 In 2 ml. of benzene was dissolved 0.41 g. of trans-1- hydroxyQ-dimethylamino Tetralin and after adding to the solution 1 ml. of benzene solution containing 0.33 g.
  • the reaction mixture was cooled and extracted with 10 ml. of water.
  • the extract was adjusted to a weak basic state with potassium carbonate and then extracted with 10 ml. of benzene.
  • the extract was dried over anhydrous magnesium sulfate and the solvent was distilled off to provide 0.37 g. of an oily material.
  • 0.17 g. of oily trans-l-benzoyloxy-Z-dimethylamino Tetralin was obtained.
  • oily trans-1-benzoyloxy-2-dimethylamino Tetralin hydrochloride was obtained.
  • Example 3 'siis'peiision 1 ml. of'benzene solution "containing O.l4..g.
  • Example 4 To 0.55 g. of trans-Z-amino-l-hydroxyindane were added 0.2 g. of sodium formate, 2 ml. of 85% formic acid and 1.5 ml. of 37% formalin and the mixture was refluxed for 8 hours. The reaction mixture was concentrated under reduced pressure and the residue was mixed with 10ml. of water. The aqueous solution prepared above was adjusted to a Weak basic state with potassium carbonate and the product was extracted with 30 ml. of chloroform. After drying the extract over anhydrous magnesium sulfate, the solvent was distilled oil to obtain an oily residue. The residue was dissolved in 3 ml. of pyridine and after adding to the solution 0.5 g.
  • Example 5 In 5 ml. of dichloromethane was dissolved 0.7 g. of 1- hydroxy-Z-dimethylaminobenzocycloheptane prepared by dimethylating 2-amino-1-hydroxybenzocycloheptane and after-adding to the solution 0.6 g. of benzoyl'chloride, the mixture was refluxed for 4 hours. The solvent was distilled off from the reaction mixture and then after adding to the residue thus obtained 10 ml. of 1 N sodium carbonate, the product was extracted three times each time with. 10ml. of benzene. The benzene extracts were washed with water and dried-over anhydrous potassium carbonate, and the benzene Was distilled off. By purifying the residue by means of a silica gel column chromatography,
  • Example 7 In 10 ml. of benzene was dissolved 1.8 g. of 2-die'thyl amino-l-hydroxyindane prepared by ethylating 2 ethyl amino-l-hydroxyindane and after adding to the solution 1.4 g. of benzoyl chloride, the mixture was refluxed for 4 hours. After cooling the reaction mixture, the crystals precipitated Were recovered by filtration and recrystallized from an ethanol-ethyl acetate to obtain 2.5 g. of 1- benzoyloxy-Z-diethylaminoindane hydrochloride having a melting point of 197-198 C. (decomposed).
  • Example 8 In 10 ml. of dichloromethane was dissolved 0.7 g. of cis-l-hydroxy-2-dimethylamino Tetralin and after adding to the solution 0.8 g. of 4-dimethylaminobenzoylchloride hydrochloride, the mixture was refluxed for 8 hours and then the solvent was distilled off under reduced pressure. A small amount of water was added to the residue thus obtained and the crystals precipitated were recovered by filtration to obtain 0.8 g. of cis-Z-dimethylamino-l-(4- dimethylaminobenzoyloxy Tetralin hydrochloride. By recrystallizing the product from an ethanol-ethyl acetate solvent, the pure crystals of the product having a melting point of 2l5-216 C. (decomposed) were obtained.
  • Example 9 In 27.5 ml. of dichloromethane was dissolved 1.9 g. of cis-1-hydroxy 2 dimethylamino Tetralin and after adding to the solution 2.8 g. of 4-acetamino-5-chloro-2- methovybenzoylchloride, the mixture was refluxed for 8 hours. The solvent was distilled off under reduced pressure and after adding to the residue thus obtained ,100 ml. of 0.1 N sodium carbonate, the product was extracted three times each time with 20 ml. of ethyl acetate. The extract was dried over anhydrous potassium carbonate and then the solvent was distilled oif under reduced pressure. By purifying the residue by means of a silica gel column chromatography, 2 g. of oily cis-1-(4-acetamino-5 chloro-2-methoxybenzoyloxy) 2-dimethylamino Tetralin was obtained.
  • Example 10 In 13 ml. of dichloromethane was dissolved 0.9 g. of cis-1-hydroxy-2-dimethylamino Tetralin and after adding to the solution 1 g. of 2-methoxy-4-nitrobenzoylchloride, the mixture was refluxed for 3 hours. The solvent was distilled off under reduced pressure and 1 ml. of ethanol and 10 ml. of ether were added to the residue obtained. The crystals thus precipitated were recovered by filtration and washed with ether to obtain 1.8 g. of cis-l- (2-methoxy-4 nitrobenzoyloxy) 2 dimethylamino Tetralin hydrochloride. By recrystallizing the product from ethanol, the pure crystals having a melting point of 207- 208 C. (decomposed) were obtained.
  • Example 11 In 5 ml. of dichloromethane was dissolved 1 g. of cisl-hydroxy-2-dimethylamino Tetralin and after adding to the solution 1 g. of p-toluoylchloride, the mixture was allowed to stand overnight. The solvent was distilled oft under reduced pressure and then 5 ml. of benzene was added to the residue. The crystals thus precipitated were recovered by filtration to obtain 1.5 g. of cis-Z-dimethylamino-l-p-toluoyloxy Tetralin hydrochloride. By recrystallizing the product from an ethanol-ether solvent, the pure crystals having a melting point of 187-189 C. (decomposed) were obtained.
  • Example 12 By following the same procedure as in Example 11 using 1 g. of cis-l-hydroxy-Z-dimethylamino Tetralin and 1.1 g. of 3,4-dichlorobenzoylchloride, 1.8 g. of cis-1-(3,4-
  • Example 13 By following the same procedure as in Example 11 using 1 g. of cisl-hydroxy-Z-dimethylamino Tetralin and 1.1 g. of p-nitrobenzoylchloride, there was obtained 1.5 5 g. of cis-Z-dimethylamino-l-(p-nitrobenzoyloxy) Tetralin hydrochloride having a melting point of 173-175 C. (decomposed).
  • Example 14 In 6.4 ml. of dichloromethane was dissolved 0.44 g. of cisl-hydroxy-Z-dimethylamino Tetralin and after adding to the solution 0.5 g. of p-phenylbenzoylchloride, the mixture was refluxed for 4 hours. The reaction mixture was, then, treated as in Example 11 to obtain 0.8 g. of cis-Z-dimethylamino-l-(p-phenylbenzoyloxy) Tetralin hydrochloride. The crystals of the product recrystallized from isopropanol had a melting point of 210-212" C. (decomposed).
  • Example 15 By following the same procedure as in Example 14 using 1.6 g. of cis-l-hydroxy-Z-dimethylamino Tetralin and 2.3 g. of 3,4,S-trimethoxybenzoylchloride, there was ob-- tained 3.6 g. of cis-1-(3,4,5-trimethoxybenzoyloxy)-2-dimethylamino Tetralin hydrochloride having a melting point of 147-149 C. (decomposed).
  • Example 16 In 5 ml. of dichloromethane was dissolved 0.462 g. of cis-l-hydroxy-Z-dimethylamino Tetralin and after adding to the solution 0.5 g. of o-methoxybenzoyl chloride, the mixture was refluxed for 5 hours. The solvent was distilled off from the reaction mixture under reduced pressure and the residue thus obtained was mixed with 10 ml. of benzene and 10 ml. of water followed by shaking. The aqueous layer thus formed was recovered and after making alkaline the aqueous layer with the addition of potassium carbonate, the product was extracted twice each time with 10 ml. of ether.
  • Example 17 By following the same procedure as in Example 16 using 2 g. of the cis-2-diethylamino-1-hydroxy Tetralin prepared by ethylating cis-2-ethylamino-1-hydroxy Tetralin and 1.42 g. of benzoylchloride, 2.5 g. of oily l-benzoyloxy-2-diethylamino Tetralin hydrochloride was obtained.
  • Example 18 A mixture of l g. of cis-2-dimethylamino-l-(p-nitrobenzoyloxy) Tetralin, 1 g. of iron powder, 10 ml. of ethanol, 3 ml. of water, and two drops of concentrated hydrochloric acid was heated to C. for 25 minutes with stirring and then after adding to the mixture 0.5 g. of sodium bicarbonate, undissolved materials were filtered off. Then, ethanol was distilled off from the filtrate under reduced pressure, the crystals thus precipitated were recovered by filtration to provide 0.5 g. of cis-l-(p-aminobenzoyloxy)-2-dimethylamino Tetralin. The crystals of the product purified by recrystallizing from benzene had a melting point of 160-161" C.
  • Example 19 By following the same procedure as in Example 18 using 1.5 g. of cis-1-(2-methoxy-4-nitrobenzoyloxy)-2-dimethylamino Tetralin hydrochloride, 0.9 g. of cis-l-(4- amino-2-methoxybenzoyloxy)-2 dimethylamino Tetralin having a melting point of 202203 C. was obtained.
  • Example 20 To a mixture of 2 ml. of formic acid and 2 ml. of 37% formalin was added 2 g. of cis-2-phenyl-3a,4,5,9btetrahydronaphtho[2,1-d] oxazole and the mixture was heated to -105 C. for 8 hours. The reaction mixture was mixed with 10 ml. of water and after making the mixture alkalin with aqueous sodium carbonate solution, the product was extracted with 20 ml., 10 ml., and then, 10 ml. of ether successively. The-ether extracts were combined and dried over anhydrous magnesium sulfate. After adding to the mixture ethanol-hydrogenchloride, the sol- Vent. was distilled off to obtain 0.97 g. of cis-l-benzoyloxy- Z-dimethylamino Tetralin hydrochloride havin a melting point of 211-212 C.
  • Example 21 To 2 g. of cis-Z-amino-l-benzoyloxy Tetralin sulfate, were added 2 ml. of formic acid, 2 ml. of formaline, and 0.45 g. of sodium formate and the mixture was heated to 105 C. for 8 hours. After making the reaction mixture alkaline with the addition of aqueous sodium carbonate solution, the product was extracted with 20 ml. and then 10 ml. of chloroform. The extracts were combined with each other and dried over anhydrous magnesium sulfate. After adding to the solution ethanol-hydrogenchloride, the solvent was distilled olf to obtain 1.3 g. of the crystals of cis-1-benzoyloxy-2-dimethylamino Tetralin hydrochloride having a melting point of 211212 C.
  • the free base form of the hydrochloride was used as the sample of the analysis by the nuclear magnetic resonance spectra.
  • the melting point of the product was 148-149 C.
  • Example 22 In 27.5 ml. of dichloromethane was dissolved 1.9 g. of cis-1-hydroxy-2-dimethylamino Tetralin and after adding to the solution 1.9 g. of cinnamoyl chloride, the mixture was refluxed for 3 hours. The solvent was distilled olf under reduced pressure from the reaction mixture and the residue was mixed with 2 ml. of benzene, 2 ml. of ethyl acetate, 10 ml. of ether, and 1 ml. of-water. The crystals precipitated were recovered by filtration and washed with ether to obtain 3.25 g. of cis-l-cinnamoyloxy-Z-dimethylamino Tetralin hydrochloride. The crystals recrystallized from Water had a melting point of 100-105 C.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
US00262623A 1971-06-22 1972-06-14 Novel 1-benzoyloxy-2-lower alkylamino-benzocycloalkane derivatives Expired - Lifetime US3823181A (en)

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JP46044491A JPS516669B1 (2) 1971-06-22 1971-06-22
JP9849571A JPS4867274A (2) 1971-12-06 1971-12-06
JP10004971A JPS4864060A (2) 1971-12-10 1971-12-10

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US (1) US3823181A (2)
CA (1) CA984851A (2)
DE (1) DE2229359A1 (2)
ES (1) ES404115A1 (2)
FR (1) FR2143304B1 (2)
GB (1) GB1360119A (2)
SE (1) SE384854B (2)

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GB9315600D0 (en) * 1993-07-28 1993-09-08 Smithkline Beecham Plc Compounds
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SE384854B (sv) 1976-05-24
FR2143304B1 (2) 1976-09-17
GB1360119A (en) 1974-07-17
ES404115A1 (es) 1976-01-01
DE2229359A1 (de) 1973-01-11
FR2143304A1 (2) 1973-02-02

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